JPS63239269A - 1,4-dihydro-4-oxoquinoline compound and its production - Google Patents
1,4-dihydro-4-oxoquinoline compound and its productionInfo
- Publication number
- JPS63239269A JPS63239269A JP62290757A JP29075787A JPS63239269A JP S63239269 A JPS63239269 A JP S63239269A JP 62290757 A JP62290757 A JP 62290757A JP 29075787 A JP29075787 A JP 29075787A JP S63239269 A JPS63239269 A JP S63239269A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- general formula
- formulas
- bromo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 1,4-dihydro-4-oxoquinoline compound Chemical class 0.000 title claims description 21
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 7
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract description 10
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 abstract 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 abstract 1
- 239000010499 rapseed oil Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 239000013078 crystal Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 10
- 239000007810 chemical reaction solvent Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OPOFPVOALIOZBR-UHFFFAOYSA-N 1-fluoroquinolin-4-one Chemical compound C1=CC=C2N(F)C=CC(=O)C2=C1 OPOFPVOALIOZBR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 235000019484 Rapeseed oil Nutrition 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- ROBKVGDBQLURAF-UHFFFAOYSA-N 1,4-dihydroquinoline Chemical compound C1=CC=C2CC=CNC2=C1 ROBKVGDBQLURAF-UHFFFAOYSA-N 0.000 description 2
- ZPMKGKUWDFEBFB-UHFFFAOYSA-N 2-bromo-4-chloro-5-fluoroaniline Chemical compound NC1=CC(F)=C(Cl)C=C1Br ZPMKGKUWDFEBFB-UHFFFAOYSA-N 0.000 description 2
- QNKQNJJCNWUOHC-UHFFFAOYSA-N 2-bromo-5-chloro-4-fluoroaniline Chemical compound NC1=CC(Cl)=C(F)C=C1Br QNKQNJJCNWUOHC-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 2
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- XJDDLMJULQGRLU-UHFFFAOYSA-N 1,3-dioxane-4,6-dione Chemical compound O=C1CC(=O)OCO1 XJDDLMJULQGRLU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MAMRRASCBCVQHO-UHFFFAOYSA-N 2-bromo-4,5-dichloroaniline Chemical compound NC1=CC(Cl)=C(Cl)C=C1Br MAMRRASCBCVQHO-UHFFFAOYSA-N 0.000 description 1
- BUTIDJREEDINSI-UHFFFAOYSA-N 2-bromo-4,5-difluoroaniline Chemical compound NC1=CC(F)=C(F)C=C1Br BUTIDJREEDINSI-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- LLWADFLAOKUBDR-UHFFFAOYSA-N 2-methyl-4-chlorophenoxybutyric acid Chemical compound CC1=CC(Cl)=CC=C1OCCCC(O)=O LLWADFLAOKUBDR-UHFFFAOYSA-N 0.000 description 1
- BYZXOYSEYWCLOK-UHFFFAOYSA-N 6-fluoro-1h-quinolin-4-one Chemical compound C1=C(F)C=C2C(O)=CC=NC2=C1 BYZXOYSEYWCLOK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- ZCILODAAHLISPY-UHFFFAOYSA-N biphenyl ether Natural products C1=C(CC=C)C(O)=CC(OC=2C(=CC(CC=C)=CC=2)O)=C1 ZCILODAAHLISPY-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- BQHDXNZNSPVVKB-UHFFFAOYSA-N diethyl 2-methylidenepropanedioate Chemical compound CCOC(=O)C(=C)C(=O)OCC BQHDXNZNSPVVKB-UHFFFAOYSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
星東上五皿里方１
本発明は、下記一般式［■］：
（式中、Ｘ及びＹは同−又は異なってフッ素原子又は塩
素原子を夫々表わす。）
で示される１、４−ジヒドロ−４−オキソキノリン化合
物（以下単に「本発明化合物［Ｉ］」という）及びその
製造法に関する。[Detailed Description of the Invention] Hoshitojo Gosara Rikata 1 The present invention is represented by the following general formula [■]: (In the formula, X and Y are the same or different and represent a fluorine atom or a chlorine atom, respectively.) The present invention relates to a 1,4-dihydro-4-oxoquinoline compound (hereinafter simply referred to as "the compound of the present invention [I]") and a method for producing the same.
嚢米Ω返ヨ
本発明化合物［Ｉ］は本発明者らにより初めて合成され
たものであり、公知文献未記載の化合物でおる。The compound [I] of the present invention was synthesized for the first time by the present inventors, and is a compound that has not been described in any known literature.
明が 決しようとする。ｌ 慮
本発明化合物［Ｉ］は、本発明者らの一部はかにより開
発中の新規な９−ハロゲン−５−アルキル−８−無置換
乃至三置換ピペラジニル−ベンゾ［ｉｊ］キノリジン−
２−カルボン酸系抗菌剤の製造中間体として有用である
。Ming tries to decide. l Considered, the compound [I] of the present invention is a novel 9-halogen-5-alkyl-8-unsubstituted to trisubstituted piperazinyl-benzo[ij]quinolidine- which is currently being developed by the present inventors.
It is useful as an intermediate in the production of 2-carboxylic acid antibacterial agents.
同 点を解決するための≦
本発明化合物［Ｉ］は、下記一般式［■］：（式中、Ｘ
及びＹは前記と同意義である。）で示されるアニリン化
合物と、２，２−ジメチル−１，３−ジオキサン−４，
６−シオン及びオルトギ酸エチルとを反応させ、下記一
般式［■］：（式中、Ｘ及びＹは前記と同意義である。In order to solve the same point, the compound [I] of the present invention has the following general formula [■]: (wherein, X
and Y have the same meanings as above. ) and 2,2-dimethyl-1,3-dioxane-4,
6-Sion and ethyl orthoformate are reacted to form the following general formula [■]: (wherein, X and Y have the same meanings as above).
）で示される化合物に変換しく以下ａ工程という）、こ
の化合物［ＩＩＩ］をついで加熱閉環する（以下す工程
という）ことにより製造することができる。) can be produced by converting the compound [III] into a compound represented by (hereinafter referred to as step a), and then subjecting this compound [III] to ring closure by heating (hereinafter referred to as step a).
ａ工程の反応は、無溶媒又は反応溶媒中、２０〜１１０
℃、好ましくは５０〜１１０’Ｃで、１５分〜１０時間
、好ましくは３０分〜５時間行う。The reaction in step a is carried out without a solvent or in a reaction solvent at a concentration of 20 to 110
C., preferably 50 to 110'C, for 15 minutes to 10 hours, preferably 30 minutes to 5 hours.
反応）容媒としては、メタノール、エタノール、プロピ
ルアルコール、ベンゼンもしくはトルエン又はこれらの
二種以上からなる混合液などが挙げられる。アニリン化
合物［ｎ］に対する使用量は、２．２−ジメチル−１，
３−ジオキサン−４，６−シオン及びオルトギ酸エチル
ともに、１〜６倍モル、好ましくは１〜３倍モルとする
。同じく反応溶媒は０．５〜２０倍重量、好ましくは１
〜１０倍重量とする。Examples of the reaction medium include methanol, ethanol, propyl alcohol, benzene, toluene, and a mixture of two or more thereof. The amount used for the aniline compound [n] is 2,2-dimethyl-1,
Both 3-dioxane-4,6-sion and ethyl orthoformate are used in 1 to 6 moles, preferably 1 to 3 moles. Similarly, the reaction solvent is 0.5 to 20 times the weight, preferably 1
~10 times the weight.
ｂ工程の加熱閉環反応は、ａ工程で得られる化合物［１
］を、伝熱媒体中、１２０〜３００℃、好ましくは１７
０〜２６０℃で、２分〜５時間、好ましくは５分〜２時
間行う。伝熱媒体としては、ダウサームＡ（ビフェニル
とジフェニルエーテルとの混合物）又はナタネ油などが
挙げられ、その使用量は、化合物［ＤＩ］に対して１〜
５０＠重量、好ましくは２〜ｉｎ重量とする。The heating ring-closing reaction in step b is the compound [1] obtained in step a.
] in a heat transfer medium at 120-300°C, preferably 17
It is carried out at 0 to 260°C for 2 minutes to 5 hours, preferably 5 minutes to 2 hours. Examples of the heat transfer medium include Dowtherm A (a mixture of biphenyl and diphenyl ether) or rapeseed oil, and the amount used is 1 to 100% of the compound [DI].
50@wt, preferably 2-in.wt.
また、本発明化合物［Ｉ］は、前記一般式［ＩＩ］で示
されるアニリン化合物とエトキシメチレンマロン酸ジエ
チルとを反応させ、下記一般式［ＩＶ］：（式中、Ｘ及
びＹは前記と同意義である。）で示される化合物を生成
しく以下Ｃ工程という）、この化合物［ＩＶ］を加熱閉
環して下記一般式［Ｖ］（式中、Ｘ及びＹは前記と同意
義である。）で示される化合物に変換しく以下Ｃ工程と
いう）、ついでこの化合物［Ｖ］を加水分解しく以下Ｃ
工程という）、最後に脱炭酸する（以下ｆ工程という）
ことによっても製造することができる。In addition, the compound [I] of the present invention can be obtained by reacting the aniline compound represented by the general formula [II] with diethyl ethoxymethylenemalonate, and producing the following general formula [IV]: (wherein, X and Y are the same as above. (hereinafter referred to as C step), this compound [IV] is ring-closed by heating to form the following general formula [V] (wherein, X and Y have the same meanings as above). (hereinafter referred to as C step), and then this compound [V] is hydrolyzed (hereinafter referred to as C step).
process), and finally decarboxylation (hereinafter referred to as f process)
It can also be manufactured by
Ｃ工程の反応は、無溶媒又は反応溶媒中、２０〜１９０
’Ｃ１好ましくは６０〜１５０’Ｃで、１〜１０時間、
好ましくは２〜６時間行う。反応溶媒としては、メタノ
ール、エタノール、プロピルアルコール、ベンゼン、ト
ルエン、酢酸エチル、Ｎ。The reaction in step C is carried out without a solvent or in a reaction solvent at a reaction temperature of 20 to 190
'C1 preferably at 60-150'C for 1-10 hours,
Preferably it is carried out for 2 to 6 hours. As a reaction solvent, methanol, ethanol, propyl alcohol, benzene, toluene, ethyl acetate, N.
Ｎ−ジメチルホルムアミドもしくはジメチルスル小キシ
ド又はこれらの二種以上からなる混合液が挙げられる。Examples include N-dimethylformamide, dimethyl sulfide, or a mixture of two or more thereof.
エトキシメチレンマロン酸ジエチルは、アニリン化合物
［ＩＩ］に対して１〜５倍モル、好ましくは１〜２倍モ
ル使用する。反応溶媒を用いる場合、その反応溶媒の使
用量は、アニリン化合物［ｎ］に対して１〜５０倍重量
、好ましくは３〜２０倍重量とする。Diethyl ethoxymethylene malonate is used in a molar amount of 1 to 5 times, preferably 1 to 2 times, the amount of aniline compound [II]. When a reaction solvent is used, the amount of the reaction solvent used is 1 to 50 times, preferably 3 to 20 times the weight of the aniline compound [n].
Ｃ工程の加熱閉環反応は、Ｃ工程で得られる化合物［Ｉ
Ｖ］ヲ、伝熱媒体中、２００〜３ＱＯ℃、好ましくは２
５０〜２８０’Ｃで、１０分〜１０時間、好ましくは３
０分〜３時間行う。伝熱媒体としては、ダウサームＡ又
はナタネ油などが挙げられ、その使用量は、化合物［Ｉ
Ｖ］に対して１〜５０（８重量、好ましくは２〜１０倍
重量とする。The heating ring-closing reaction in Step C is performed on the compound [I
V] 200-3QO℃ in a heat transfer medium, preferably 2
50-280'C, 10 minutes-10 hours, preferably 3
Do this for 0 minutes to 3 hours. Examples of the heat transfer medium include Dowtherm A or rapeseed oil, and the amount used is determined by the amount of the compound [I
V] to 1 to 50 (8 weight, preferably 2 to 10 times the weight).
Ｃ工程の加水分解反応は、酸又はアルカリの過剰量を用
い、反応溶媒中、０〜１２０℃、好ましくは使用反応溶
媒の還流温度で、１５分〜１０時間、好ましくは３０分
〜３時間行う。酸としては希塩酸または希硫酸などが、
アルカリとしては水酸化ナトリウム又は水酸化カリウム
の水溶液がそれぞれ挙げられる。反応溶媒としては、メ
タノール、エタノール、プロピルアルコール、ジオキサ
ン又は酢酸などが挙げられる。なお、反応溶媒の使用量
は、前工程で得られる化合物［Ｖ］に対して１〜５０倍
重量、好ましくは５〜１０倍重量とする。The hydrolysis reaction in step C is carried out using an excess amount of acid or alkali in a reaction solvent at 0 to 120°C, preferably at the reflux temperature of the reaction solvent used, for 15 minutes to 10 hours, preferably 30 minutes to 3 hours. . Examples of acids include dilute hydrochloric acid or dilute sulfuric acid.
Examples of the alkali include aqueous solutions of sodium hydroxide and potassium hydroxide, respectively. Examples of the reaction solvent include methanol, ethanol, propyl alcohol, dioxane, and acetic acid. The amount of the reaction solvent to be used is 1 to 50 times, preferably 5 to 10 times the weight of the compound [V] obtained in the previous step.
ｆ工程の脱炭酸反応は、Ｃ工程で得られる固形物を、伝
熱媒体中、２００〜３００℃、好ましくは２５０〜２８
０℃で、１０分〜１０時間、好ましくは３０分〜３時間
行う。伝熱媒体としては、ダウサームＡ又はナタネ油な
どが挙げられ、その使用量はＣ工程で得られる化合物［
Ｖ］に対して１〜５０倍重口、好ましくは２〜１０（８
重量とする。In the decarboxylation reaction in step f, the solid obtained in step C is heated at 200 to 300°C, preferably 250 to 28°C, in a heat transfer medium.
The treatment is carried out at 0°C for 10 minutes to 10 hours, preferably 30 minutes to 3 hours. Examples of the heat transfer medium include Dowtherm A or rapeseed oil, and the amount used is determined by the amount of the compound obtained in step C [
V], 1 to 50 times heavier, preferably 2 to 10 times heavier (8
Weight.
なお、ａ工程及びＣ工程において、原料となるアニリン
化合物［ＩＩ］は、下記反応工程式Ａに従って製造する
ことができる。In addition, in step a and step C, the aniline compound [II] serving as a raw material can be produced according to the following reaction scheme A.
反応工程式Ａ
（アニリン化合物［■］〉
（反応工程式中、Ｘ及びＹは前記と同意義でおる。）
１１及ｌ旦皿り皇１
本発明化合物［Ｉ］は、例えば下記反応工程式Ｂに従い
、抗菌剤として有用な下記一般式［ＸＩＩＩ］の９−ハ
ロゲン−５−アルキル−８−無置換乃至三置換ピペラジ
ニル−ベンゾ［ｉｊｌキノリジン−２−カルボン酸化合
物に誘導され得る。Reaction Scheme A (Aniline Compound [■]> (In the Reaction Scheme, X and Y have the same meanings as above.) According to B, a 9-halogen-5-alkyl-8-unsubstituted to trisubstituted piperazinyl-benzo[ijlquinolidine-2-carboxylic acid compound of the following general formula [XIII] useful as an antibacterial agent can be derived.
（以下余白）
（反応工程式中、Ｒ１は低級アルキル基を、Ｒ２はメチ
ル基又はエチル基を、Ｒ３はメチル基、エチル基又はメ
トキシエチル基を夫々表わし、Ｒ４はメチル基、エチル
基又はプロピル基を、Ｒ５はメチル基又はエチル基を夫
々表わし、Ｒ６は水素原子、炭素数１〜３個のアルキル
基又は２−ヒドロキシエチル基を表わし、Ｒ及びＲ８は
同−又は異なって水素原子、メチル基又はエチル基を夫
々表わし、ここでＲ８はＲ７が結合する同一炭素に結合
していてもよく、Ｘ及びＹは同−又は異なってフッ素原
子又は塩素原子を夫々表わし、×１及びＸ３は臭素原子
又はヨウ素原子を夫々表わし、Ｘ２は塩素原子又は臭素
原子を表わす。）本発明を実施例をもって更に説明する
。(Left below) (In the reaction scheme, R1 represents a lower alkyl group, R2 represents a methyl group or ethyl group, R3 represents a methyl group, ethyl group or methoxyethyl group, and R4 represents a methyl group, ethyl group or propyl group. R5 represents a methyl group or an ethyl group, R6 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a 2-hydroxyethyl group, and R and R8 are the same or different and represent a hydrogen atom, a methyl group, or ethyl group, respectively, where R8 may be bonded to the same carbon to which R7 is bonded, X and Y are the same or different and represent a fluorine atom or a chlorine atom, respectively, and x1 and X3 are bromine or an iodine atom, respectively, and X2 represents a chlorine atom or a bromine atom.) The present invention will be further explained with reference to Examples.
実施例１
（ａ工程） １〜ルエン９００ｄに、２−ブロモ−５−
クロロ−４−フルオロアニリン４４９．０Ｉｊ（２，０
０モル）、２，２−ジメチル−１゜３−ジオキサン−４
，６−ジオン３１７．０び（２，２０モル）及びオルト
ギ酸エチル３４０． ＥＥＦ（２，３０モル）を加え、
３０分間、加熱還流した。Example 1 (Step a) 1 to 900d of toluene, 2-bromo-5-
Chloro-4-fluoroaniline 449.0Ij (2,0
0 mol), 2,2-dimethyl-1゜3-dioxane-4
, 317.0 of 6-dione (2.20 mol) and 340.0 of ethyl orthoformate. Add EEF (2,30 mol),
The mixture was heated to reflux for 30 minutes.
この反応液を氷冷し、析出した固形物を濾取し、ついで
少量のメタノールで洗浄し、５−（２−ブロモ−５−ク
ロロ−４−フルオロアニリノメチレン）−２，２−ジメ
チル−１，３−ジオキサン−４，６−ジオンの無色結晶
７４９．６ｇ（収率９９％）を得た。融点は２０１〜２
０３℃（分解）でおった。The reaction solution was cooled on ice, and the precipitated solid was collected by filtration, washed with a small amount of methanol, and 5-(2-bromo-5-chloro-4-fluoroanilinomethylene)-2,2-dimethyl- 749.6 g (yield: 99%) of colorless crystals of 1,3-dioxane-4,6-dione were obtained. Melting point is 201-2
03°C (decomposition).
（ｂ工程） 上述の結晶６０５．８ｔｊ（１，６０モル
）を、予め１８５°Ｃに加熱しておいたダウサームＡの
１８６０ｄに一度に加え、１７５〜１８５℃で１５分間
撹拌した。この反応液を空温まで冷却したのち更に氷冷
し、これにベキサン１８６０戒を注ぎ撹拌した。ついで
析出した固形物を濾取し、少量の酢酸エチルで洗浄し、
８−ブロモ−５−クロロ−６−フルオロ−４−オキソ−
１，４−ジヒドロキノリンの無色結晶３５０．８ｙ （
収率７９％）を得た。融点は２３０〜２３２℃でおった
。(Step b) 605.8tj (1.60 mol) of the above crystals were added at once to Dowtherm A 1860d which had been heated to 185°C in advance, and stirred at 175-185°C for 15 minutes. This reaction solution was cooled to air temperature and then further cooled on ice, and Bexane 1860 was poured into it and stirred. Then, the precipitated solid was collected by filtration, washed with a small amount of ethyl acetate,
8-bromo-5-chloro-6-fluoro-4-oxo-
Colorless crystals of 1,4-dihydroquinoline 350.8y (
A yield of 79% was obtained. The melting point was 230-232°C.
１日−核磁気共鳴スペクトル、（ＣＦ３ ＧＯＯＤ。1st - Nuclear magnetic resonance spectrum, (CF3 GOOD.
δ）ニ
ア、５０（ＩＨ，ｄ）、 ８．２３（１Ｎ、ｄ）、 ８
．８３（ＩＨ，ｄ）実施例２
上述の実施例１において、ａ工程の２−ブロモ−５−ク
ロロ−４−フルオロアニリンを２−ブロモー４，５−ジ
クロロアニリン４８１．９ｇ（２，００モル）に変更し
た以外はほぼ同様に操作し、８−ブロモ−５，６−ジク
ロロ−４−オキソ−１，４−ジヒドロキノリンの無色結
晶３８０．９３を得た。融点は１８３〜１８５℃でめっ
た。δ) Near, 50 (IH, d), 8.23 (1N, d), 8
．． 83 (IH, d) Example 2 In the above Example 1, 2-bromo-5-chloro-4-fluoroaniline in step a was replaced with 481.9 g (2,00 mol) of 2-bromo-4,5-dichloroaniline. The procedure was carried out in almost the same manner except that 380.93 of a colorless crystal of 8-bromo-5,6-dichloro-4-oxo-1,4-dihydroquinoline was obtained. The melting point was 183-185°C.
１Ｈ’ｔ＜’ａ気共１５スベ’） トＪＩ／ （ＣＦ３
Ｃ００Ｄ。1H't<'a ki 15 sube') トJI/ (CF3
C00D.
δ）ニ
ア、５１（ＩＨ，ｄ）、 ８．２２（ＩＨ，Ｓ）、 ８
．８４（ＩＨ，ｄ）Ｘ思■旦
（ａ工程） ２−ブロモ−４，５−ジフルオロアニリン
４１６．１ｇ（２，００モル）、２，２−ジメチル−１
，３−ジオキサン−４，６−シオン３３１．５ｇ（２，
３０モル）、オルトギ酸エチル３１１．２ｇ （２，１
０モル）及びトルエン８５０ｍＡを混合し、これを３０
分間加熱還流した。δ) Near, 51 (IH, d), 8.22 (IH, S), 8
．． 84 (IH, d)
,3-dioxane-4,6-sion 331.5g (2,
30 mol), ethyl orthoformate 311.2 g (2,1
0 mole) and 850 mA of toluene were mixed, and this was mixed with 30
The mixture was heated to reflux for a minute.
得られた反応液を氷冷し、析出した固形物を濾取し、つ
いで少量のエーテルで洗浄し、５− （２−ブロモ−４
，５−ジフルオロアニリノメチレン）−２，２−ジメチ
ル−１，３−ジオキサン−４゜６−ジオンの無色結晶６
８０．９９ （収率９４％）を得た。融点は１９０〜１
９２℃（分解）であった。The resulting reaction solution was ice-cooled, the precipitated solid was collected by filtration, and then washed with a small amount of ether to give 5-(2-bromo-4
, 5-difluoroanilinomethylene)-2,2-dimethyl-1,3-dioxane-4°6-dione colorless crystals 6
80.99 (yield 94%) was obtained. Melting point is 190-1
The temperature was 92°C (decomposed).
（ｂ工程） 上述の結晶５４３．３９ （１，５０モル
）をダウサームＡの１．６．ｌ！に懸濁し、この懸濁液
を撹拌下に３０分間で２５０℃まで昇温させた。ついで
この反応液を氷冷し、これにエーテル１．６Ｎを注ぎ入
れ、析出した固形物を濾取した。(Step b) The above crystal 543.39 (1,50 mol) was mixed with 1.6 mol of Dowtherm A. l! The temperature of this suspension was raised to 250° C. for 30 minutes while stirring. Next, this reaction solution was cooled with ice, 1.6N of ether was poured into it, and the precipitated solid was collected by filtration.
この固形物を少量のエーテルで洗浄し、８−ブロモ−５
，６−ジフルオロ−４−オキソ−１，４−ジヒドロキノ
リンの無色結晶２３４．１ｔｊ（収率６０％）を得た。This solid was washed with a small amount of ether and 8-bromo-5
, 234.1tj (yield 60%) of colorless crystals of 6-difluoro-4-oxo-1,4-dihydroquinoline were obtained.
融点は２１２〜２１４°Ｃでめった。The melting point was 212-214°C.
１日−核磁気共鳴スペクトル（ＣＦ３ＣＯＯＤ。1 day - Nuclear magnetic resonance spectrum (CF3COOD.
δ） ニ
ア、４７（１Ｍ、ｄ）、 ８．２３（ＩＨ，ｄｄ）、
８．８０（ＩＨ，ｄ）Ｘ塵■Ａ
（Ｃ工程） ２−ブロモ−５−クロロ−４−フルオロア
ニリン４４９．Ｏび（２，００モル）とエトキシメチレ
ンマロン酸ジエチル４３２．５９（２，００モル〉とを
混和し、１３５〜１４０℃で４時間撹拌し、２−ブロモ
ー５−クロロ−４−フルオロアニリノメチレンマロン酸
ジエチルを生成させた。δ) Near, 47 (1M, d), 8.23 (IH, dd),
8.80 (IH, d) Obi (2,00 mol) and 432.59 (2,00 mol) diethyl ethoxymethylenemalonate were mixed and stirred at 135 to 140°C for 4 hours to form 2-bromo-5-chloro-4-fluoroanilino. Diethyl methylenemalonate was produced.
（ｄ工程） この反応生成液を空温まで冷却し、これに
ダウサームＡの１．６１を注ぎ、２６５〜２７０℃で４
時間撹拌した。この反応液を氷冷し、ついでこれにエー
テル３．２．１！を加えて撹拌した。(Step d) This reaction product liquid was cooled to air temperature, 1.61 of Dowtherm A was poured into it, and 4
Stir for hours. This reaction solution was cooled on ice, and then 3.2.1! of ether was added to it. was added and stirred.
析出した固形物を濾取し、少量のエーテルで洗浄し、８
−ブロモ−５−クロロ−３−エトキシカルボニル−６−
フルオロ−４−オキソ−１，４−ジヒドロキノリンの無
色粉末４６０．１９（収率６６％）を得た。The precipitated solid was collected by filtration, washed with a small amount of ether, and
-bromo-5-chloro-3-ethoxycarbonyl-6-
460.19 (yield: 66%) of colorless powder of fluoro-4-oxo-1,4-dihydroquinoline was obtained.
（Ｃ工程） 上述の粉末３４８．６ｆｆ （１，００−
Ｅル）をエタノール１４００ｄに懸濁し、これに２０％
水酸化ナトリウム水溶液７２０ｒｎｉを注ぎ、１．５時
間、加熱還流した。この反応液を氷水７００ｄに注ぎ、
濃塩酸にてｐＨ’ｌに調整した。(Step C) 348.6ff of the above powder (1,00-
Suspend Ele) in 1400d of ethanol and add 20%
720 rni of sodium hydroxide aqueous solution was poured into the mixture, and the mixture was heated under reflux for 1.5 hours. Pour this reaction solution into 700 d of ice water,
The pH was adjusted to 1 with concentrated hydrochloric acid.
析出した結晶性粉末を濾取し、ついで水洗し、乾燥した
。The precipitated crystalline powder was collected by filtration, then washed with water and dried.
（ｆ工程） この結晶性粉末の全量をダウサームＡの１
０１００Ｏに懸濁し、２６５〜２７０℃で１時間撹拌し
た。この反応液を氷冷し、エーテル１０００ｍを加えて
撹拌し、′析出した固形物を濾取した。得られた固形物
を少量のエーテルで洗浄し、８−ブロモ−５−クロロ−
６−フルオロ−４−オキソ−１，４−ジヒドロキノリン
の無色結晶２４６．１ｇ（収率８９％）を得た。この結
晶の融点は２３０〜２３２°Ｃであり、′Ｈ−核磁気共
鳴スベクトルは実施例１に記載した数値と全く一致した
。(Step f) The entire amount of this crystalline powder is
0100O and stirred at 265-270°C for 1 hour. The reaction solution was ice-cooled, 1000 ml of ether was added and stirred, and the precipitated solid was collected by filtration. The resulting solid was washed with a small amount of ether to give 8-bromo-5-chloro-
246.1 g (yield: 89%) of colorless crystals of 6-fluoro-4-oxo-1,4-dihydroquinoline were obtained. The melting point of this crystal was 230-232°C, and the 'H-Nuclear Magnetic Resonance Svector was completely consistent with the value described in Example 1.
Ｘ血■支
実施例４において、Ｃ工程の２−ブロモ−５−クロロ−
４−フルオロアニリンを２−ブロモ−４゜５−ジクロロ
アニリン４８１．９ＳＪ （２，００モル）に変更した
以外（よほぼ同様に操作し、８−ブロモ−５，６−ジク
ロロ−４−オキソ−１，４−ジヒドロキノリンの無色結
晶４１０．２９を得た。In Example 4, 2-bromo-5-chloro-
8-Bromo-5,6-dichloro-4-oxo- 410.29 of a colorless crystal of 1,4-dihydroquinoline was obtained.
この結晶の融点は１８３〜１８５℃でおり、′Ｈ−核磁
気共鳴スベクトルは実施例２に記載した数値と全く一致
した。The melting point of this crystal was 183-185°C, and the 'H-nuclear magnetic resonance spectral value was completely consistent with the value described in Example 2.
割Ｏ坦
（Ｃ工程）２−ブロモ−４，５−ジフルオロアニリン４
１６．１ｇ（２，００モル）をエトキシメチレンマロン
酸ジエチル４３２．５ｇ（２，００モル）に加え、１２
０〜１２５℃で６時間撹拌し、２−ブロモ−４，５−ジ
フルオロアニリノメチレンマロン酸ジエチルを生成させ
た。Split O-flat (C step) 2-bromo-4,5-difluoroaniline 4
16.1 g (2,00 mol) was added to 432.5 g (2,00 mol) of diethyl ethoxymethylenemalonate, and 12
The mixture was stirred at 0 to 125° C. for 6 hours to produce diethyl 2-bromo-4,5-difluoroanilinomethylenemalonate.
（ｄ工程） この反応生成液を予め２７０℃に加熱して
おいたダウサームＡの１．５ｆＩに徐々に注ぎ、２６５
〜２７０℃で１．５時間撹拌した。(Step d) This reaction product liquid was gradually poured into 1.5 fI of Dowtherm A which had been heated to 270°C in advance.
Stir at ~270°C for 1.5 hours.
この反応液を氷冷し、これにエーテル１．５ｇを撹拌下
に加え、析出した固形物を濾取した。この固形物を少量
のエーテルで洗浄し、８−ブロモ−５，６−ジフルオロ
−３−エトキシカルボニル−４−オキソ−１，４−ジヒ
ドロキノリンの無色粉末４２５．１ｇ（収率６４％）を
得た。This reaction solution was ice-cooled, 1.5 g of ether was added thereto with stirring, and the precipitated solid was collected by filtration. This solid was washed with a small amount of ether to obtain 425.1 g (yield: 64%) of a colorless powder of 8-bromo-5,6-difluoro-3-ethoxycarbonyl-4-oxo-1,4-dihydroquinoline. Ta.
（Ｃ工程） 得られた粉末３３２．１ ｇ（１，００モ
ル）をエタノール１４００ｍ１に懸濁し、２０％水酸化
ナトリウム水溶液６９０ｒｒｉｉを加え、２時間加熱還
流した。この反応液を氷水４．５１に注ぎ、濃塩酸にて
ｐＨ１に調整し、ついで調整液中に析出した結晶性粉末
を濾取、水洗、乾燥した。(Step C) 332.1 g (1,00 mol) of the obtained powder was suspended in 1400 ml of ethanol, 690 rrii of a 20% aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 2 hours. This reaction solution was poured into ice water (4.5%), adjusted to pH 1 with concentrated hydrochloric acid, and then the crystalline powder precipitated in the adjusted solution was collected by filtration, washed with water, and dried.
（ｆ工程） この結晶性粉末の全量をダウサームＡの１
０００ｒＩＪ１に懸濁し、これを２６５〜２７０℃で１
時間撹拌した。得られた反応液を水冷し、これにエーテ
ル１０００ｒｒ１１を撹拌下に加え、析出し−た固形物
を濾取した。この固形物を少量のエーテルで洗浄し、８
−ブロモ−５，６−ジフルオロ−４−オキソ−１，４−
ジヒドロキノリンの無色結晶２２６．３９（収率８７％
）を得た。この結晶の融点は２１２〜２１４℃であり、
′Ｈ−核磁気共鳴スベクトルは実施例３に記載した数値
と全く一致した。(Step f) The entire amount of this crystalline powder is
000rIJ1 and incubate it at 265-270°C.
Stir for hours. The resulting reaction solution was cooled with water, 1,000 rr of ether was added to it with stirring, and the precipitated solid was collected by filtration. This solid was washed with a small amount of ether and
-bromo-5,6-difluoro-4-oxo-1,4-
Colorless crystals of dihydroquinoline 226.39 (yield 87%)
) was obtained. The melting point of this crystal is 212-214°C,
The 'H-Nuclear Magnetic Resonance vector was completely consistent with the values described in Example 3.
釆厘恩ｌ
（Ｃ工程）２−ブロモ−４−クロロ−５−フルオロアニ
リン４４９．０ｇ（２，００モル）、２゜２−ジメチル
−１，３−ジオキサン−４，６−シオン３１７．０！？
（２，２０モル）、オルトギ酸エチル３４０．８ｇ（
２，３０モル）及びエタノール９００威を混合し、これ
を３０分間加熱還流した。この反応液を氷冷し、析出し
た固形物を濾取し、ついで少量のエタノールで洗浄し、
５−（２−ブロモ−４−クロロ−５−フルオロアニリノ
メチレン）−２，２−ジメチル−１，３−ジオキサン−
４，６−ジオンの無色結晶７１９．３９（収率９５％）
を得た。融点は１９７〜１９９℃（分解）であった。(Step C) 449.0 g (2,00 mol) of 2-bromo-4-chloro-5-fluoroaniline, 317.0 g (2,00 mol) of 2゜2-dimethyl-1,3-dioxane-4,6-sion ! ?
(2.20 mol), ethyl orthoformate 340.8 g (
2.30 moles) and 900 moles of ethanol were mixed, and the mixture was heated under reflux for 30 minutes. The reaction solution was cooled on ice, the precipitated solid was collected by filtration, and then washed with a small amount of ethanol.
5-(2-bromo-4-chloro-5-fluoroanilinomethylene)-2,2-dimethyl-1,3-dioxane-
Colorless crystals of 4,6-dione 719.39 (yield 95%)
I got it. The melting point was 197-199°C (decomposed).
（ｂ工程）上述の結晶５６７．９９ （１，５０モル）
をダウサームＡの１７００ｄに懸濁し、２００〜２１０
℃で３０分間撹拌した。この反応液を氷冷し、これにヘ
キサン１７００ｄを注ぎ撹拌した。ついで析出した固形
物を濾取し少量のエタノールで洗浄し、８−ブロモ−６
−クロロ−５−フルオロ−４−オキソ−１，４−ジヒド
ロキノリンの無色結晶２９６．（１（収率７２％）を得
た。融点は２２５〜２２７℃でおった。(Step b) Above crystal 567.99 (1,50 mol)
suspended in Dowtherm A 1700d, 200-210
Stirred at ℃ for 30 minutes. This reaction solution was ice-cooled, and 1700 d of hexane was poured into it and stirred. Then, the precipitated solid was collected by filtration and washed with a small amount of ethanol to obtain 8-bromo-6.
Colorless crystals of -chloro-5-fluoro-4-oxo-1,4-dihydroquinoline 296. (1 (yield 72%)) The melting point was 225-227°C.
１日−核磁気共鳴スペクトル（ＣＦ３ＣＯＯＤ。1 day - Nuclear magnetic resonance spectrum (CF3COOD.
δ）ニ
ア、４９（ＩＨ，ｄ）、８．２３（１？ｌ、ｄ）、８．
８２（ＩＨ，ｄ）１思Ｕ
（Ｃ工程）２−ブロモ−４−クロロ−５−フルオロアニ
リン４４９．０ｇ（２，００モル）とエトキシメチレン
マロン酸ジエチル４３２．５ｆｆ（２，００モル）とを
混和し、１３０〜１３５℃で５時間撹拌し、２−ブロモ
ー４−クロロ−５−フルオロアニリノメチレンマロン酸
ジエチルを生成させた。δ) Near, 49 (IH, d), 8.23 (1?l, d), 8.
82 (IH, d) 1 U (Step C) 449.0 g (2,00 mol) of 2-bromo-4-chloro-5-fluoroaniline and 432.5 ff (2,00 mol) of diethyl ethoxymethylenemalonate. were mixed and stirred at 130-135°C for 5 hours to produce diethyl 2-bromo4-chloro-5-fluoroanilinomethylenemalonate.
（Ｃ工程）この反応液にダウサームＡの１．６１を注ぎ
２６５〜２７０℃で３時間撹拌した。この反応液を氷冷
し、ついでこれにエーテル１．６１を加えて撹拌した。(Step C) 1.61 of Dowtherm A was poured into this reaction solution and stirred at 265 to 270°C for 3 hours. This reaction solution was ice-cooled, and then 1.61 g of ether was added thereto and stirred.
析出した固形物を濾取し、少量のエーテルで洗浄し、８
−ブロモ−６−クロロ−３−エトキシカルボニル−５−
フルオロ−４−オキソ−１，４−ジヒドロキノリンの無
色粉末４８８．０ｇ（収率７０％）を得た。The precipitated solid was collected by filtration, washed with a small amount of ether, and
-bromo-6-chloro-3-ethoxycarbonyl-5-
488.0 g (yield 70%) of colorless powder of fluoro-4-oxo-1,4-dihydroquinoline was obtained.
（ｅ工程）上述の粉末３４８．６ｙ （１，００モル）
をエタノール１４００ｍに懸濁し、これに２０％水駿化
ナトリウム水溶液７００ｍ１を加え２時間加熱還流した
。この反応液を氷水１４００１ｄに注ぎ、濃塩酸にてｐ
Ｉ−１１に調整した。析出した結晶性粉末を濾取し、つ
いで水洗し乾燥した。(Step e) Above powder 348.6y (1,00 mol)
was suspended in 1,400 ml of ethanol, 700 ml of a 20% aqueous sodium hydroxide solution was added thereto, and the mixture was heated under reflux for 2 hours. This reaction solution was poured into ice water 14001d, and the solution was purified with concentrated hydrochloric acid.
Adjusted to I-11. The precipitated crystalline powder was collected by filtration, then washed with water and dried.
（ｆ工程）この結晶性粉末の全量をダウサームＡの１０
１００Ｏに懸濁し、２６５〜２７０℃で１時間撹拌した
。この反応液を氷冷し、エーテル１０００ｄを加えて撹
拌し、析出した固形物を濾取した。得られた固形物を少
量のエーテルで洗浄し、８−ブロモ−６−クロロ−５−
フルオロ−４−オキソ−１，４−ジヒドロキノリンの無
色結晶２２６、７ｇ（収率８２％）を得た。この結晶の
融点は２２５〜２２７℃であり、′Ｈ−核磁気共鳴スベ
クトルは実施例７に記載した数値と全く一致した。(Step f) The total amount of this crystalline powder is 10% of Dowtherm A.
The mixture was suspended at 100O and stirred at 265-270°C for 1 hour. This reaction solution was ice-cooled, 1000 d of ether was added and stirred, and the precipitated solid was collected by filtration. The resulting solid was washed with a small amount of ether to give 8-bromo-6-chloro-5-
226.7 g (yield: 82%) of colorless crystals of fluoro-4-oxo-1,4-dihydroquinoline were obtained. The melting point of this crystal was 225 to 227°C, and the 'H-nuclear magnetic resonance spectral value was completely consistent with the value described in Example 7.
Claims (3)
素原子を夫々表わす。） で示される１，４−ジヒドロ−４−オキソキノリン化合
物。(1) General formula [I]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, X and Y are the same or different and represent a fluorine atom or a chlorine atom, respectively.) 1, 4 represented by -dihydro-4-oxoquinoline compound.
素原子を夫々表わす。） で示されるアニリン化合物と、２，２−ジメチル−１，
３−ジオキサン−４，６−ジオン及びオルトギ酸エチル
とを反応させ、一般式［III］：▲数式、化学式、表等
があります▼［III］ （式中、Ｘ及びＹは前記と同意義である。）で示される
化合物に変換し、この化合物をついで加熱閉環すること
を特徴とする一般式［ I ］：▲数式、化学式、表等が
あります▼［ I ］ （式中、Ｘ及びＹは前記と同意義である。）で示される
１，４−ジヒドロ−４−オキソキノリン化合物の製造法
。(2) General formula [II]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, X and Y are the same or different and represent a fluorine atom or a chlorine atom, respectively.) ,2,2-dimethyl-1,
By reacting 3-dioxane-4,6-dione and ethyl orthoformate, the general formula [III]: ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ [III] (In the formula, X and Y have the same meanings as above. General formula [I]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, X and Y are A method for producing a 1,4-dihydro-4-oxoquinoline compound shown in (same meaning as above).
素原子を夫々表わす。） で示されるアニリン化合物と、エトキシメチレンマロン
酸ジエチルとを反応させ、一般式［IV］：▲数式、化学
式、表等があります▼［IV］ （式中、Ｘ及びＹは前記と同意義である。）で示される
化合物を生成し、この化合物を加熱閉環して一般式［Ｖ
］： ▲数式、化学式、表等があります▼［Ｖ］ （式中、Ｘ及びＹは前記と同意義である。）で示される
化合物に変換し、ついでこの化合物を加水分解し、最後
に脱炭酸することを特徴とする一般式［ I ］： ▲数式、化学式、表等があります▼［ I ］ （式中、Ｘ及びＹは前記と同意義である。）で示される
１，４−ジヒドロ−４−オキソキノリン化合物の製造法
。(3) General formula [II]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, X and Y are the same or different and represent a fluorine atom or a chlorine atom, respectively.) , and ethoxymethylene diethyl malonate to form a compound represented by the general formula [IV]: ▲Mathematical formula, chemical formula, table, etc.▼[IV] (wherein, X and Y have the same meanings as above) This compound is ring-closed by heating to form the general formula [V
]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[V] (In the formula, General formula [I] characterized by carbonation: ▲There are mathematical formulas, chemical formulas, tables, etc.▼1,4-dihydro represented by [I] (wherein, X and Y have the same meanings as above) - A method for producing a 4-oxoquinoline compound.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27668486 | 1986-11-21 | ||
| JP61-276684 | 1986-11-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63239269A true JPS63239269A (en) | 1988-10-05 |
| JPH046707B2 JPH046707B2 (en) | 1992-02-06 |
Family
ID=17572877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62290757A Granted JPS63239269A (en) | 1986-11-21 | 1987-11-19 | 1,4-dihydro-4-oxoquinoline compound and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63239269A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995023787A1 (en) * | 1994-03-01 | 1995-09-08 | Ishihara Sangyo Kaisha, Ltd. | Process for producing 5,7-dichloro-4-hydroxyquinoline |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5758668A (en) * | 1980-07-28 | 1982-04-08 | Dynamit Nobel Ag | Manufacture of quinoline, naphthyridine and other nitrogen-bi-heterocyclic compound |
-
1987
- 1987-11-19 JP JP62290757A patent/JPS63239269A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5758668A (en) * | 1980-07-28 | 1982-04-08 | Dynamit Nobel Ag | Manufacture of quinoline, naphthyridine and other nitrogen-bi-heterocyclic compound |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995023787A1 (en) * | 1994-03-01 | 1995-09-08 | Ishihara Sangyo Kaisha, Ltd. | Process for producing 5,7-dichloro-4-hydroxyquinoline |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH046707B2 (en) | 1992-02-06 |
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